Researchers at Texas A&M University have identified MAP4K4, a protein involved in multiple biological pathways, as a therapeutic target for metabolic dysfunction-associated steatohepatitis (MASH) and developed an experimental small-molecule inhibitor that simultaneously reduced fat accumulation, inflammation, liver injury, and fibrosis in preclinical models. The findings are published in JHEP Reports.
MASH is a progressive form of fatty liver disease in which excess hepatic fat triggers inflammation and tissue damage, potentially advancing to cirrhosis, liver failure, and the need for transplantation. Although the first approved medications for MASH have recently become available, they are indicated only for advanced-stage disease and carry common side effects, leaving a significant treatment gap for patients at earlier stages of progression.
The research team found that MAP4K4 levels increased as MASH advanced, suggesting its activity drives disease progression. Working with collaborators at the University of Oklahoma, they tested GPPD, a compound that selectively inhibits MAP4K4 activity without reducing its overall expression levels. This approach is intended to preserve the protein’s normal physiological functions while interrupting its role in disease-related pathways, potentially minimising unintended side effects.
In preclinical models, GPPD attenuated all major hallmarks of MASH simultaneously, an outcome the researchers describe as significant given that most experimental therapies address only a single aspect of the disease. The team also identified a previously uncharacterised signalling pathway through which MAP4K4 influences disease progression, which may point to additional therapeutic targets.
Preclinical toxicology studies have shown no evidence of significant toxicity. Pharmacokinetic studies are currently under way to determine optimal dosing for future clinical trials. The researchers are also investigating whether the therapeutic effects are direct or partly mediated through weight loss observed during treatment.
Source: Ampadu F et al. A novel pharmacological inhibitor of MAP4K4 activity attenuates metabolic dysfunction-associated steatohepatitis. JHEP Reports (2026). DOI: 10.1016/j.jhepr.2026.101886
